Dry powder inhaler and methods of use

ABSTRACT

Methods for reducing the risk of a thromboembolic event, and a related drug delivery system are provided. In some embodiments, a dose of acetylsalicylic acid can be provided in powder form to a patient using a dry powder inhaler. The dose can be effective to reduce a risk of a thromboembolic event in a patient. A dry powder inhaler used for the method can have a mouthpiece, a reservoir for receiving the dose of acetylsalicylic acid, and an actuation member for making available the dose of acetylsalicylic acid for inhalation by a patient through the mouthpiece.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/740,407, filed Dec. 20, 2012, the entirety of which is incorporatedherein by reference.

FIELD

The subject technology relates generally to apparatuses and methods fordelivery of substances, e.g., delivery of medication to the lungs usingby inhalation for treating disease.

SUMMARY

An aspect of at least one embodiment disclosed herein includes therecognition of a need for improved apparatuses and methods for deliveryof drugs for treating disease that utilize a dosage that is effective toreduce a risk of a thromboembolic event in a patient, lower thantraditional dosages, and administered using a more direct deliverymechanism to the systemic blood stream.

Thromboembolic Symptoms and Events

A thromboembolic event, such as myocardial infarction, deep venousthrombosis, pulmonary embolism, thrombotic stroke, etc., can presentwith certain symptoms that allow a patient or clinician to provide aninitial therapy or treatment for the event. In some situations, a babyaspirin (81 mg) or a regular aspirin (330 mg) may be orally administeredin order to provide an initial treatment for the patient.

According to some embodiments disclosed herein is the realization thatthis treatment may not act as quickly as necessary to provide asufficient therapeutic effect and therefore, may lead to a lesspreferred outcome. Thus, in some embodiments, a drug delivery system andrelated methods are disclosed that provide an accelerated and moreefficient pathway and treatment for reducing the risk of athromboembolic event and/or providing treatment for a thromboembolicevent. For example, some embodiments provide systems and methods ofadministering a nonsteroidal anti-inflammatory drug (“NSAID”) byinhalation, such as by a dry powder inhaler (“DPI”) or a metered doseinhaler (“MDI”).

Delivery Mechanisms for Drugs

Drugs can be administered orally in different ways, such as liquids,capsules, tablets, or chewable tablets. The oral route is used mostoften because it is the most convenient, safest, and least expensive.However, oral drug delivery has limitations because of the way a drugtypically moves through the digestive tract.

For example, when a drug is administered orally, it is absorbed in themouth, stomach, and the small intestine. Before the drug enters thebloodstream, it must pass through the intestinal wall and travels to theliver. While passing through the intestinal wall and liver, the drug ismetabolized, which can decrease the amount of the drug that actuallyreaches the bloodstream. The metabolism of the drug reduces thebioavailability of the drug and is often termed the “first pass effect.”The fraction of the drug lost during due to the first pass effect isgenerally determined by absorption in the liver and gut wall, andgastrointestinal lumen enzymes, gut wall enzymes, bacterial enzymes, andhepatic (liver) enzymes.

Generally, the first pass effect on aspirin significantly reduces thebioavailability of the administered dosage. For example, due to theacidic conditions in the stomach, aspirin is absorbed in the stomach andthe upper small intestine. After being absorbed, aspirin is metabolizedto acetic acid and salicylate. When taken orally, generally only aboutone to two-thirds of the dose of aspirin is bioavailable due to thefirst pass effect.

For example, in Iwamoto K., GASTROINTESTINAL AND HEPATIC FIRST-PASSMETABOLISM OF ASPIRIN IN RATS, J Pharm Pharmacol. 1982 March; 34(3), pp.176-80, the entirety of which is incorporated herein by reference, thestudy examines the absorption of aspirin in four male subjects followingan oral solution of 650 mg. As stated in the study report, “theabsorption process appeared to follow first-order kinetics, with ahalf-life ranging from 4.5 to 16.0 min. between subjects. Comparison ofthe area under the aspirin plasma concentration-time curve followingintravenous and oral routes indicated that only 68% of the dose reachedthe peripheral circulation intact.”

The applicant has determined that even drugs that are administered byinhalation undergo a first pass effect. For drug administration byinhalation, smaller particles proceed via a nasal route, down thewindpipe (trachea) and into the lungs. The size of the particles can bedeterminative of the overall efficacy of the treatment. Once inside thelungs, these particles are absorbed into the bloodstream.

Few drugs are administered by inhalation because the dosage of aninhaled drug, as well as the delivery timing, can often be difficult tomeasure. Usually, this method is used to administer drugs that actspecifically on the lungs, such as aerosolized antiasthmatic drugs inmetered-dose containers, and to administer gases used for generalanesthesia.

Pharmacokinetics of Aspirin

Aspirin is the acetylated form of salicylic acid, and the activechemical in aspirin is called acetylsalicylic acid (ASA). Aspirin isused by millions of people to achieve desirable effects, and by manypeople, aspirin is used daily in doses of 81 mg (i.e., a baby aspirin).The principal effect of aspirin is to impair the function ofcyclooxygenase enzymes (specifically, COX1 and COX2 enzymes).

By inhibiting COX1, aspirin can irreversibly inhibit plateletaggregation, which decreases the risk of blood clots. Additionally, theimpairment of the COX2 enzyme can reduce inflammation, stiffness, andpain in the body by inhibiting prostaglandins and thromboxanes. As such,individuals at high risk for heart attack, stroke, or with inflammationoften take aspirin to address symptoms and effects of these conditions.As noted, aspirin can effectively reduce the likelihood of suchmyocardial events and reduce pain and inflammation with a dose as smallas 81 mg. However, due at least in part to its inhibition of COX1,aspirin can increase the risk of bleeding and cause damage to organssuch as the stomach and intestines, which can be painful.

Dry Powder Inhaler Technology

As stated above, the oral delivery of aspirin may create a risk ofdamage to the stomach wall leading to pain, indigestion and a high riskof bleeding. Further, according to at least one of the aspects ofembodiments disclosed herein is the realization that it is oftendifficult to orally administer a drug during emergency situations thatmay implicate or result in a thromboembolic event. For example, thepatient may be experiencing vomiting or otherwise be unable to take thedrug orally. Additionally, oral administration of a drug may beundesirable because the drug does not reach the systemic blood streamimmediately, thus delaying the important effects of the drug. Even so,due to the first pass effect in the liver and gut, the amount of drugreaching systemic circulation is much less than that administered.Therefore, according to aspects of various embodiments disclosed hereinis the realization that an alternative route of administration couldavoid these unwanted side-effects.

Various embodiments disclosed herein reflect the novel realization thatdelivery of a drug by inhalation in the early stages of an emergencysituation can provide a fast-acting, effective form of preliminarytreatment of certain medical conditions. For example, in someembodiments, upon receiving a complaint of a symptom of a seriousthromboembolic event, a patient can be administered, by DPI, atherapeutic amount of a NSAID. The NSAID can address problems associatedwith or provide an initial treatment for the medical condition.

However, dry powder inhalation of drugs has generally been limited bycough, to dosages of less than a milligram. Recent developments inparticle engineering, in particular the development of PulmoSphere™technology, have enabled the delivery of a larger amount of dry powderto delivered to the lungs in a single actuation. See David E. Geller,M.D., et al., DEVELOPMENT OF AN INHALED DRY-POWDER FORMULATION OFTOBRAMYCIN USING PULMOSPHERE™ TECHNOLOGY, J Aerosol Med Pulm Drug Deliv.2011 August; 24(4), pp. 175-82, the entirety of which is incorporatedherein by reference. In this publication, a dose of 112 mg tobramycin(in four capsules) was effectively delivered via PulmoSpheres™.

In accordance with some embodiments is the realization that the bodyincludes various particle filters that limit the efficacy of inhaleddrugs. For example, the oropharynx tends to prevent passage of particleshaving a diameter greater than 5 μm. However, in order to reach thealveoli, particles must have a size from about 1 μm to about 5 μm.Accordingly, some embodiments herein disclose the preparation and use ofinhalable aspirin using technology similar to PulmoSpheres™ to produceparticles with a median geometric diameter of from about 1 μm to about 5μm, and in some embodiments, from about 1.7 μm to about 2.7 μm.

There has been no single dose use of aspirin by dry powder inhaler toreplace the traditional daily use of a NSAID (such as a 81 mg babyaspirin) or emergency use of a NSAID as preventative care for symptomsof a thromboembolic event. Accordingly, some embodiments disclosedherein provide methods for administering a NSAID by dry powderinhalation in an amount less than the dosage of a baby aspirin (i.e.,less than 81 mg).

Therefore, in some embodiments, a method for treating disease, e.g., byreducing the risk of a thromboembolic event, can be provided, whichcomprises administering a NSAID, such as a salicylate, by a DPI or MDI.For example, the method can comprise administering acetylsalicylic acidby a DPI or MDI. The administered dosage can be much less than about 80mg of acetylsalicylic acid, and can be less than or equal to about 30 mgof acetylsalicylic acid.

For example, according to some embodiments, the dose can be from about 5mg to about 75 mg. In some embodiments, the dose can be from about 10 mgto about 60 mg. The dose can be from about 15 mg to about 50 mg.Further, in some embodiments, the dose can be from about 20 mg to about40 mg. In some embodiments, the dose can be about 30 mg. Such dosagescan provide a bioequivalent dosage when compared to typical dosages of81 mg to about 325 mg, while demonstrating few negative side effects.

Thus, in some embodiments, a NSAID, such as aspirin, can be administeredby DPI or MDI in a single dose that is much less than a traditional oraldose of aspirin, which can provide an bioequivalent equivalent treatmentwhile tending to avoid the negative side effects associated with someNSAIDs, such as aspirin. Further, systems of administering suchtreatments are also provided.

The DPI or MDI can have a mouthpiece and an actuation member for makingavailable the NSAID for inhalation by a patient to reduce the risk ofthe thromboembolic event. For example, the amount of the doseadministered can comprise less than about 80 mg of acetylsalicylic acid.

For example, according to some embodiments, a method of reducing therisk of a thromboembolic event is provided and can compriseadministering a dose of a nonsteroidal anti-inflammatory drug by a drypowder inhaler. The dose can be effective to reduce a risk of athromboembolic event in a patient. The dry powder inhaler can have amouthpiece and an actuation member for making available the dose of thenonsteroidal anti-inflammatory drug for inhalation by the patient toreduce the risk of the thromboembolic event. The amount of the doseadministered comprises less than about 80 mg of the nonsteroidalanti-inflammatory drug.

A drug delivery system can also be provided according to someembodiments, for treating a disease, for example, by reducing the riskof a thromboembolic event. The system can comprise a dose of anonsteroidal anti-inflammatory drug in powder form. The dose can beeffective to reduce a risk of a thromboembolic event in a patient. Thesystem can also comprise a dry powder inhaler. The dry powder inhalercan have a mouthpiece, a reservoir for receiving the dose of thenonsteroidal anti-inflammatory drug, and an actuation member for makingavailable the dose of the nonsteroidal anti-inflammatory drug forinhalation by the patient through the mouthpiece. Further, the amount ofthe dose of the nonsteroidal anti-inflammatory drug comprises less thanabout 80 mg of the nonsteroidal anti-inflammatory drug.

In some embodiments, the thromboembolic event comprises at least one ofmyocardial infarction, deep venous thrombosis, pulmonary embolism, orthrombotic stroke. The dose of the nonsteroidal anti-inflammatory drugcan be administered as a preliminary treatment in response to a symptomof a thromboembolic event. The nonsteroidal anti-inflammatory drug cancomprise aspirin. Further, the dose of the nonsteroidalanti-inflammatory drug can be administered in a single dose.

The dose of the acetylsalicylic acid can comprise an amount from about 5mg to about 75 mg. The dose of the acetylsalicylic acid can comprisefrom about 10 mg to about 60 mg. The dose of the acetylsalicylic acidcan comprise from about 20 mg to about 40 mg. The dose of theacetylsalicylic acid can comprise from about 25 mg to about 35 mg.Further, the dose of the acetylsalicylic acid can comprise about 30 mg.

Additional features and advantages of the subject technology will be setforth in the description below, and in part will be apparent from thedescription, or may be learned by practice of the subject technology.The advantages of the subject technology will be realized and attainedby the structure particularly pointed out in the written description andclaims hereof as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology asclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide furtherunderstanding of the subject technology and are incorporated in andconstitute a part of this specification, illustrate aspects of thesubject technology and together with the description serve to explainthe principles of the subject technology.

FIG. 1 is a schematic view of a patient using a dry powder inhaler, inaccordance with some implementations of the methods and systemsdisclosed herein.

FIGS. 2A-F illustrate usages and a configuration of a dry powderinhaler, according to some embodiments.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a full understanding of the subject technology. It willbe apparent, however, to one ordinarily skilled in the art that thesubject technology may be practiced without some of these specificdetails. In other instances, well-known structures and techniques havenot been shown in detail so as not to obscure the subject technology.

A phrase such as “an aspect” does not imply that such aspect isessential to the subject technology or that such aspect applies to allconfigurations of the subject technology. A disclosure relating to anaspect may apply to all configurations, or one or more configurations.An aspect may provide one or more examples of the disclosure. A phrasesuch as “an aspect” may refer to one or more aspects and vice versa. Aphrase such as “an embodiment” does not imply that such embodiment isessential to the subject technology or that such embodiment applies toall configurations of the subject technology. A disclosure relating toan embodiment may apply to all embodiments, or one or more embodiments.An embodiment may provide one or more examples of the disclosure. Aphrase such “an embodiment” may refer to one or more embodiments andvice versa. A phrase such as “a configuration” does not imply that suchconfiguration is essential to the subject technology or that suchconfiguration applies to all configurations of the subject technology. Adisclosure relating to a configuration may apply to all configurations,or one or more configurations. A configuration may provide one or moreexamples of the disclosure. A phrase such as “a configuration” may referto one or more configurations and vice versa.

As discussed above, although NSAIDs, such as aspirin, can providevarious beneficial effects and contribute to reducing the likelihood ofa thromboembolic event, there may be some drawbacks to their use.Further, the use of NSAIDs, such as aspirin, in a clinical setting hastraditionally been limited to oral administration. Oral administrationof aspirin, for example, can result in the loss or inactivation ofapproximately ⅔ of the oral dosage due to the first pass effect in thegut and liver. While one third of the dosage reaches the systemic bloodstream and provides the desired effect, the negative side effectscreated by the full dosage often deter patients from using aspirin on aregular or daily basis.

Further, in many situations, such as in emergencies, oral administrationof NSAIDs, such as aspirin, may be inappropriate because it may take toolong to be effective. According to at least one aspect of someembodiments disclosed herein is the realization that an alternativeadministration method and systems can be implemented that utilize alower dosage and provide a more direct delivery mechanism to thesystemic blood stream. Thus, some embodiments disclosed herein allow forthe beneficial effects of NSAIDs, such as aspirin, to be achieved on aregular basis and in emergency situations, while minimizing previousdrawbacks associated with the use of NSAIDs.

Various studies have determined that aspirin has a significant effect onreducing the risk of myocardial infarction. However, these studiespresented inconclusive data on strokes, pulmonary embolism, or deepvenous thrombosis. These studies have used aspirin dosages of 325 mg,However, these studies have based their findings on oral administrationof aspirin and have not suggested DPI or MDI pathways, which areprovided in some embodiments disclosed herein. Further, theadministration of aspirin has negative side effects, such assignificantly increasing major gastrointestinal and extracranial bleedsby over 50%. This has led some to argue that for preventative treatment,aspirin is of uncertain net value.

Further studies have tested whether the benefits of aspirin could beobtained at low dosages, such as that of baby aspirin (i.e., 81 mg). TheSwedish Aspirin Low-dose Trial (SALT) found that a low dose (75 mg/day)of aspirin significantly reduces the risk of stroke or death in patientswith cerebrovascular ischaemic events. However, the study also reportedgastrointestinal side-effects that included a significant excess ofbleeding episodes. A Danish study found that patients receiving aspirinas an antithrombotic agent achieved satisfactory platelet inhibitionwith 50 mg/day, while the remainder of the patients needed over 50mg/day. Furthermore, a Dutch TIA Study concluded that aspirin at anydose above 30 mg daily prevents 13% of vascular events, and that thereis a need for more efficacious drugs. There continues to be significantdebate about the efficacy of very low doses of aspirin. However, nostudy or teaching has been provided regarding the administration ofaspirin by DPI or MDI at very low doses.

Additionally, the applicant notes that although inhaled dry powderformulations of aspirin have been developed, reports have stated thatthe formulation was not clinically feasible because it is difficult tomeet the high dosage requirements of aspirin (˜80 mg/day for low-doseprevention of coronary events and stroke, and at least 300 mg/day forpain or fever relief) via pulmonary delivery of dry powders.

In addition, these reports recognize that adverse effects of dry powderon the lungs, such as coughing, cannot be avoided unless the doses areless than a few tenths of a milligram in a single breath. Thus, priorteachings suggest that higher dosage requirements of aspirin would beimpossible to meet using DPI. Finally, some have taught that there is ahigher incidence of aspirin intolerance in asthmatic patients whenaspirin is delivered by inhalation than orally.

In yet another study, the authors noted that use of nanoparticulatedrugs for dry powder inhaler (DPI) delivery is not straightforward.Direct inhalation of nanoparticulate drugs was infeasible due to theirsmall size. The nanometer size leads to the nanoparticulate drugs beingpredominantly exhaled from the lungs, without any deposition takingplace. Moreover, a severe aggregation problem arising from the smallsize makes their physical handling difficult for DPI delivery.Accordingly, “large hollow carrier particles” of nanoparticulate drugshas been developed for pulmonary delivery of some drugs. See Hadinoto etal., Drug Release Study Of Large Hollow Nanoparticulate AggregatesCarrier Particles For Pulmonary Delivery, International Journal ofPharmaceutics 341 (2007) 195-20, the entirety of which is incorporatedby reference herein.

In the Hadinoto study, the authors used aspirin as a model for “lowlywater-soluble” drugs. The authors acknowledged that “with regard to theaspirin, the nanoparticulate polymer delivery method is not the mostsuitable method of delivery due to the high dosage requirement ofaspirin (˜300 mg/day),” and overall, the aim of the study was toidentify key facets in the formulation of the large hollownanoparticulate aggregates. See id.

In some embodiments of the inventions disclosed herein, methods andsystems are provided for treating a disease, for example, by reducingthe risk of a thromboembolic event by administration of a very lowamount of a NSAID, such as a low dose of aspirin, by DPI or MDI. Thedose can be much less than that of a baby aspirin (less than 81 mg). Forexample, the dose can be from about 5 mg to about 75 mg. In someembodiments, the dose can be from about 8 mg to about 60 mg. The dosecan be from about 10 mg to about 50 mg. Further, in some embodiments,the dose can be from about 15 mg to about 40 mg. In some embodiments,the dose can be about 18 mg or about 20 mg. Such dosages can provide abioequivalent dosage when compared to typical dosages of 81 mg to about325 mg, while demonstrating few negative side effects.

Referring to FIG. 1, in a dry powder inhalation technique, a patient canuse a dry powder inhaler 10 to inhale a powder formulation of a drug,such as a NSAID. The dose is effective to reduce a risk of athromboembolic event in the patient. An aspect of some embodiments isthe realization that because the lung is an efficient filter, itgenerally only permits particles having a size of less than 5 μm. Forexample, after the drug enters the main stem bronchus 20, the drug willenter each lung 22, 24. The drug can then pass through the bronchialtrees 26, 28 until reaching the individual alveoli 30 in the lungs 22,24, which are exceedingly numerous, as discussed below. Of each longThus, the dry powder inhaler 10 can allow the patient to self administera dosage of particles having a size of from about 1 μm and about 5 μm.In some embodiments, the particle size can be from about 2 μm to about 4μm.

According to some embodiments, various types of inhalers can be used toprovide the drug using a DPI or MDI delivery system. The doseadministered can be effective to reduce a risk of a thromboembolic eventin a patient.

For example, the dry powder inhaler 10 can comprise a mouthpiece, areservoir for receiving the NSAID, and an actuation member for makingavailable the NSAID for inhalation by a patient through the mouthpiece.

For example, FIGS. 2A-2F illustrate a DPI delivery device 100 having amouthpiece 102 and a drug compartment 104. The drug compartment 104 canbe inserted into an inhaler body cavity 110.

For example, as shown in FIG. 2B, the drug compartment 104 can beinserted into the body cavity 110 into a stowed position 120 for storagepurposes. However, the drug compartment 104 can also be moved to a firstposition 122, shown in FIG. 2C, in which a first receptacle 140 of thedrug compartment 104 is aligned with a mouthpiece airway 142. In thisfirst position 122, the drug contained in the first receptacle 140 canbe delivered through the mouthpiece airway 142 to be inhaled by thepatient, as illustrated in FIG. 2D.

Additionally, as shown in FIG. 2E, the drug compartment 104 can be movedto a second position 124 in which a second receptacle 144 is alignedwith the mouthpiece airway 142. Thus position, the drug contained in thesecond receptacle 144 can be inhaled by the patient, as illustrated inFIG. 2F.

In some embodiments, NSAIDs can be used in various methods and systems.In some embodiments, NSAIDs can include salicylates, i.e., the salts andesters of salicylic acid, that have anti-platelet action. Further,NSAIDs can also include one or more of the following:

Aspirin (Aspirin is a brand name; the chemical is called acetylsalicylicacid) Celecoxib (Celebrex) Dexdetoprofen (Keral) Diclofenac (Voltaren,Cataflam, Voltaren-XR) Diflunisal (Dolobid) Etodolac (Lodine, Lodine XL)Etoricoxib (Algix) Fenoprofen (Fenopron, Nalfron) Firocoxib (Equioxx,Previcox) Flurbiprofen (Urbifen, Ansaid, Flurwood, Froben) Ibuprofen(Advil, Brufen, Motrin, Nurofen, Medipren, Nuprin) Indomethacin(Indocin, Indocin SR, Indocin IV) Ketoprofen (Actron, Orudis, Oruvail,Ketoflam) Ketorolac (Toradol, Sprix, Toradol IV/IM, Toradol IM)Licofelone (under development) Lornoxicam (Xefo) Loxoprofen (Loxonin,Loxomac, Oxeno) Lumiracoxib (Prexige) Meclofenamic acid (Meclomen)Mefenamic acid (Ponstel) Meloxicam (Movalis, Melox, Recoxa, Mobic)Nabumetone (Relafen) Naproxen (Aleve, Anaprox, Midol Extended Relief,Naprosyn, Naprelan) Nimesulide (Sulide, Nimalox, Mesulid) Oxaporozin(Daypro, Dayrun, Duraprox) Parecoxib (Dynastat) Piroxicam (Feldene)Rofecoxib (Vioxx, Ceoxx, Ceeoxx) Salsalate (Mono-Gesic, Salflex,Disalcid, Salsitab) Sulindac (Clinoril) Tenoxicam (Mobiflex) Tolfenamicacid (Clotam Rapid, Tufnil) Valdecoxib (Bextra)

Other alternatives can also be used instead of a NSAID in some methodsor systems disclosed herein. Such alternatives include as Plavix(clopidogrel), COX-2 inhibitors, other remedies such as Nattokinase (anenzyme (EC 3.4.21.62, extracted and purified from a Japanese food callednattē). Further, other drugs that provide different beneficial effects,such as being effective to reduce a risk of a thromboembolic event in apatient, can also be used in some embodiments. Thus, the discussion ofmethods and systems shall apply generally to these various alternatives,although for discussion purposes, the present disclosure often refers toaspirin. It is contemplated that the methods, effects, pharmacokineticdata, and other considerations relating to aspirin can be equallyapplied to other NSAIDs, according to some embodiments.

Through some of the embodiments disclosed herein, the applicant noteshave overcome the challenges acknowledged by prior teachings. Inparticular, the applicant notes have recognized that when a drug isinhaled into the lungs, the drug can be dispersed toward the alveoli.Although alveoli primarily function to exchange carbon dioxide foroxygen, alveoli also produce enzymes. Thus, inhaled substances, such aspathogens, drugs, or other chemicals, may be processed at the alveoli.

An alveolus comprises a network of elastic fibers and capillaries,resembling a woven sphere on its outer surface. The capillaries functionto carry oxygen depleted blood toward the lungs and oxygen rich bloodaway from the lungs, via the pulmonary artery and the pulmonary vein.The interior of each alveoli comprises a thin tissue known as analveolar lining or epithelium. Alveolar epithelium is made of twodistinct types of cells, known as flat type I and type II. Flat type Icells cover most of the surface area of the epithelium and are closelyspaced, allowing only small molecules to pass therebetween, such asoxygen and carbon dioxide. Type II alveolar cells aid in producing thepulmonary surfactant used in gas exchange. Further, the alveolarepithelium also comprises macrophages, which assist in disposing of fineparticulate foreign matter such as dust, tar, and pathogens. Despite thediminutive size of the alveoli (being only approximately 250 μm),because an adult can have between 200 million and 400 million alveoli,the alveolar respiratory surface area can be from approximately 1,400 toabout 1,600 square feet.

According to some embodiments disclosed herein, absorption of NSAIDsadministered by DPI or MDI through the pulmonary capillaries andepithelium can provide an immediately effective treatment to addresssymptoms of thromboembolic events. One of the novel realizations of someembodiments is that the substantial first pass effect produced by oraladministration of NSAIDs, such as aspirin, can be avoided throughadministration by dry powder inhaler. In addition, there has hithertobeen no teaching or suggestion regarding the pharmacokinetics of drypowder delivery of a NSAID, such as aspirin, and the possible metabolismor inactivation of the drug as it encounters the endothelial tissue ofthe pulmonary capillaries.

The delivery of a NSAID by DPI or MDI is a complex and unpredictabletechnological area that has not provided straightforward or expectedresults to a person of skill in the art. Accordingly, there has been noreason for a person of skill to believe that a combination of priorsystems or treatment methods could produce the embodiments disclosedherein. For example, some embodiments herein recognize an unexpectedresult that as a drug crosses the endothelium of pulmonary arteries andalveoli, the first pass effect is minimized and results in a much lowerrate of the activation of the drug than in other drug delivery pathways.

The endothelium of the pulmonary capillaries serve as a barrier byselectively allowing materials to exit or enter the bloodstream. Itwould be expected that aspirin would be inactivated in the pulmonarycapillaries, which are lined by endothelial cells. The endothelial cellsare extremely metabolically active. Thus, a person of skill would expectthat aspirin would be inactivated by the endothelium of the pulmonarycapillaries. However, according to some embodiments disclosed herein, itis contemplated that as the powdered drug encounters the endothelium,the endothelium can metabolize or activate a much smaller portion of thepowdered drug compared to the metabolism provided by the gut and liver.For example, after being transformed in the stomach to salicylic acid,as much as 80% of the salicylic acid is metabolized in the liver. Thus,only a small minority of the salicylic acid is bioavailable to thesystemic blood stream.

However, it is contemplated that a vast majority of the salicylic acidmetabolized from the inhaled aspirin powder will be bioavailable to thesystemic blood stream. Thus, a dose of much less than that of a babyaspirin (less than 81 mg) can be provided by dry powder inhalation. Thiscan provide a much lower dosage while providing a bioequivalent dosage.

Further, in accordance an aspect of some embodiments, it is contemplatedthat an analogous first pass effect may be experienced in theendothelium of the pulmonary capillaries. Accordingly, with regard tothe provision of an inhaled dosage that is the bioequivalent of a babyaspirin administered orally, the inhaled dosage should account for somefirst pass effect experience through the endothelium of the pulmonarycapillaries.

In accordance with some embodiments, the first pass effect through theendothelium of the pulmonary capillaries can be a minimum, whichprovides little overall effect on the inhaled dosage.

For example, the dose of a NSAID, such as aspirin, can be less thanabout 80 mg. In some embodiments, the dose of a NSAID can be from about5 mg to about 75 mg. In some embodiments, the dose of a NSAID can befrom about 10 mg to about 60 mg. In some embodiments, the dose of aNSAID can be from about 20 mg to about 40 mg. In some embodiments, thedose of a NSAID can be from about 25 mg to about 35 mg. In someembodiments, the dose of a NSAID can be about 30 mg. In someembodiments, the dose of a NSAID can be about 30 mg. Further, the NSAIDcan be from about 5 mg and about 20 mg. The NSAID can be about

However, it is also contemplated that in some embodiments, the firstpass effect through the endothelium of the pulmonary capillaries can beentirely negligible. Thus, the amount of the inhaled dosage need not beadjusted to compensate for first pass effect through the pulmonarycapillaries.

Therefore, some embodiments recognize the unexpected result that evenextremely low doses of aspirin (and likely other NSAIDs) can provide asignificant therapeutic effect while providing to minimal orinconsequential side effects. For example, doses as low as 5 mg can beeffective in reducing the risk of a thromboembolic event. Accordingly,the net benefits increased dramatically at significantly lower doses,according to some embodiments. These results and outcomes are unexpectedgiven the complex and unpredictable nature of drug interactions in thebody, drug delivery pathways, and microscopic drug structures. Finally,no teachings or other prior references disclose a system or process forachieving therapeutically beneficial results while substantiallyavoiding any negative side effects using DPI or MDI drug deliverymechanisms with microscopic NSAIDs.

In accordance with some embodiments, the dry powder administration ofthe NSAID, such as a salicylate like acetylsalicylic acid, can compriseparticles having a size of from about 1 μm to about 5 μm, as discussedabove. The particles can be highly porous and demonstrate a sponge-likemorphology or be a component of a carrier particle. The particles canalso demonstrate a spheroidal shape, by which the shape and poroussurface can serve to decrease the area of contact between particles,thereby leading to less particle agglomeration and more effectivedistribution throughout the lung. Dry powder technologies, such asPulmoSphere™, may be implemented in embodiments of the methods andsystems disclosed herein.

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

As used herein, the phrase “at least one of” preceding a series ofitems, with the term “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one of each item listed; rather, the phrase allows a meaningthat includes at least one of any one of the items, and/or at least oneof any combination of the items, and/or at least one of each of theitems. By way of example, the phrases “at least one of A, B, and C” or“at least one of A, B, or C” each refer to only A, only B, or only C;any combination of A, B, and C; and/or at least one of each of A, B, andC.

Terms such as “top,” “bottom,” “front,” “rear” and the like as used inthis disclosure should be understood as referring to an arbitrary frameof reference, rather than to the ordinary gravitational frame ofreference. Thus, a top surface, a bottom surface, a front surface, and arear surface may extend upwardly, downwardly, diagonally, orhorizontally in a gravitational frame of reference.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

While certain aspects and embodiments of the invention have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the invention. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover such forms or modifications aswould fall within the scope and spirit of the invention.

What is claimed is:
 1. A method of reducing risk of a thromboembolicevent, the method consisting of the step of administering through oralinhalation to a patient in an emergency a single dose of acetylsalicylicacid formulated as a dry powder comprising dry particles, the doseeffective to reduce the risk of the thromboembolic event in the patient,by a dry powder inhaler, the dry powder inhaler having a mouthpiece andan actuation member for making available the dose of the acetylsalicylicacid for inhalation by the patient to reduce the risk of thethromboembolic event, wherein the amount of the dose administered to thepatient in the emergency comprises less than 60 mg of acetylsalicylicacid, and wherein the particles have a median geometric diameter rangingfrom 1 μm to about 5 μm.
 2. The method of claim 1, wherein the dose ofthe acetylsalicylic acid comprises an amount from about 5 mg to about 60mg.
 3. The method of claim 1, wherein the dose of the acetylsalicylicacid comprises from about 8 mg to about 60 mg.
 4. The method of claim 1,wherein the dose of the acetylsalicylic acid comprises from about 10 mgto about 40 mg.
 5. The method of claim 1, wherein the dose of theacetylsalicylic acid comprises from about 15 mg to about 30 mg.
 6. Themethod of claim 1, wherein the dose of the acetylsalicylic acidcomprises about 20 mg.
 7. The method of claim 1, wherein the dose of theacetylsalicylic acid comprises about 18 mg.
 8. The method of claim 1,wherein the dose of the acetylsalicylic acid is administered as apreliminary treatment in response to a symptom of a thromboembolicevent.
 9. A drug delivery system for reducing risk of a thromboembolicevent, the system comprising: a single dose of acetylsalicylic acid inpowder form comprising dry particles, the dose effective to reduce therisk of the thromboembolic event in a patient in an emergency; a drypowder inhaler for oral inhalation, the dry powder inhaler having amouthpiece, a reservoir for receiving the dose of acetylsalicylic acid,and an actuation member for making available the dose of theacetylsalicylic acid for inhalation by the patient through themouthpiece, wherein the dose of acetylsalicylic acid administered to thepatient in the emergency comprises less than 60 mg of acetylsalicylicacid, and wherein the particles have a median geometric diameter rangingfrom about 1 μm to about 5 μm.
 10. The system of claim 9, wherein thedose of the acetylsalicylic acid comprises an amount from about 5 mg toabout 60 mg.
 11. The system of claim 9, wherein the dose of theacetylsalicylic acid comprises from about 8 mg to about 60 mg.
 12. Thesystem of claim 9, wherein the dose of the acetylsalicylic acidcomprises from about 10 mg to about 40 mg.
 13. The system of claim 9,wherein the dose of the acetylsalicylic acid comprises from about 15 mgto about 30 mg.
 14. The system of claim 9, wherein the dose of theacetylsalicylic acid comprises about 20 mg.
 15. The system of claim 9,wherein the dose of the acetylsalicylic acid comprises about 18 mg.